Ischemic vascular disease is a major source of human morbidity and mortality, and more than half of all non-traumatic amputations in the United States occur in patients with diabetes—a major risk factor for peripheral vascular disease and amputation. Critical limb ischemia is estimated to develop in 500 to 1000 individuals per million per year. In the lower extremities, critical limb ischemia occurs when arteriogenesis is not adequate to overcome ischemia from arterial occlusive disease. In a large proportion of these patients, the anatomic extent and the distribution of arterial occlusive disease makes the patients unsuitable for operative or percutaneous revascularization. Despite advances in bypass surgery and endovascular intervention, more than 150,000 major amputations are performed in the United States due to critical limb ischemia. In other vascular beds, inadequate or maladaptive collateral artery formation leads to myocardial ischemia and infarction, stroke, mesenteric ischemia and ischemic nephropathy. Thus understanding the molecular mechanisms of collateral artery enlargement and vascular remodeling to develop new therapeutic strategies is a critical area of investigation.
Of particular interest, is the tumor suppressor protein p53. p53 is a highly conserved transcription factor involved in DNA repair, growth arrest, and apoptosis. p53 expression and activation increases in response to hypoxia, oxidative stress, and DNA damage. p53 regulates other forms of vascular remodeling, including atherosclerosis and intimal hyperplasia. The expression of p53 is increased by hindlimb ischemia and conditions associated with arterial occlusion such as diabetes and hypercholesterolemia independently induce p53 expression. Despite this substantial evidence suggesting that p53 may regulate ischemia-induced angiogenesis and arteriogenesis, the exact effect of this important stress-induced protein on these critical vascular responses to ischemia remains undefined. There is no optimal medical therapy for critical limb ischemia. Specifically, there is no pharmacological treatment for patients with tissue ischemia secondary to arterial occlusion to increase blood flow. Patients with arterial occlusive disease are treated with antiplatelet agents to prevent secondary platelet deposition, statins to prevent additional plaque buildup, and anticoagulants to prevent or treat secondary thrombosis. None of these classes of agents increase blood flow through augmentation of collateral artery enlargement and none have been shown to relieve ischemia.
In patients with tissue ischemia, because there is no pharmacological treatment, amputation, despite its associated morbidity, mortality, and functional implications, is often recommended as a solution to disabling symptoms. Therefore, it is desirable to develop novel therapies for treating of these patients. Here, the role of p53 in regulating ischemia-induced angiogenesis and arteriogenesis is defined. Potential mechanisms by which this regulation occurs in vivo has been identified. A direct negative effect of p53 on angiogenesis, arteriogenesis, and limb perfusion as well as several potential molecular mechanisms has been elucidated. It has been shown that pharmacologic modulation of p53 function improves collateral artery formation (arteriogenesis) and limb perfusion after ischemia, demonstrating the potential therapeutic benefit of inhibiting p53 to improve tissue perfusion in arterial occlusive disorders.